In a recently published article in the journal Science Immunology, scientists have described the identification and therapeutic evaluation of an antibody that broadly neutralizes major variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including the alpha, beta, delta, and omicron variants.
In response to the deadly coronavirus disease, 2019 (COVID-19) caused by SARS-CoV-2, several potential vaccines, therapeutic antibodies, and antiviral drugs have been developed, which collectively helped reduce the pandemic trajectory. However, continuous emergence of novel viral variants with increased transmissibility and immune fitness has highlighted the need for developing broad-spectrum therapeutic and preventive interventions that can neutralize a wide variety of viral variants.
Most monoclonal therapeutic antibodies developed during the early pandemic phase work by preventing the interaction between the SARS-CoV-2 spike protein and human angiotensin-converting enzyme 2 (ACE2), which is the key step for viral entry into host cells. These antibodies mostly target epitopes in the receptor-binding motif (RBM) of the spike receptor-binding domain (RBD).
The most recently emerged SARS-CoV-2 omicron variant contains more than 15 mutations in the spike RBD, which makes the variant highly resistant to monoclonal as well as vaccine-induced antibodies. To better manage the pandemic, it is vital to develop broadly neutralizing antibodies against immune evasive variants like omicron.
In the current study, scientists have described the identification and therapeutic evaluation of a monoclonal antibody with broad neutralizing efficacy against SARS-CoV-2 variants.
Identification of anti-SARS-CoV-2 monoclonal antibody
The generation of spike-targeting antibodies was performed by immunizing and subsequently boosting mice with the spike ectodomain or RBD of the original SARS-CoV-2 Wuhan strain. LIBRA (linking B cell receptor to antigen specificity through sequencing) sequencing technology was used to identify antigen-specific memory B cells and single cell sequenced B cell receptors.
The DNA encoding the variable regions of identified B cell receptors was inserted into a human immunoglobulin G1 (IgG1) antibody backbone to produce chimeric antibodies. This led to the generation of 27 RBD-targeting and seven non-RBD-targeting antibodies.
The virus neutralization assay in the study identified seven antibodies with high neutralizing efficiency against the Wuhan strain of SARS-CoV-2. Of these antibodies, one (SW186) showed the optimal neutralizing efficiency against a wide range of SARS-CoV-2 variants, including alpha, beta, delta, gamma, lambda, and mu.
The identified SW186 antibody showed high neutralizing efficacy against wild-type SARS-CoV-2 and its variants at nanomolar concentrations. However, the antibody showed significantly reduced neutralizing efficiency against omicron and its sub-variants.
Notably, the SW186 antibody showed high neutralizing efficiency against severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), a betacoronavirus responsible for the 2002-2004 outbreak of SARS. This finding indicates that the SW186 antibody targets an epitope highly conserved between SARS-CoV-1 and SARS-CoV-2.
Structural analysis of antigen-antibody complex
The cryo-electron microscopic analysis of the antibody-antigen complex revealed that SW186 antibody-targeted epitope is located outside the RBM of spike RBD. The epitope comprised several conserved amino acids. Further analysis revealed that the SW186 antibody does not bind at the RBD-ACE2 interface.
The epitope of the SW186 antibody comprised a glycosylation site (N343), which is important for viral entry into host cells. This residue is highly conserved between human coronaviruses.
Further analysis revealed that the heavy chain complementarity-determining region 3 (HCDR3) of SW186 antibody is partially inserted into an RBD minor groove and that the interactions are largely contributed by the polypeptide backbone rather than the side chains of the RBD minor groove. This finding suggests that RBD mutations might not significantly affect the binding of the SW186 antibody.
Therapeutic efficacy of SW186
The therapeutic efficacy of the antibody was tested by initially infecting the mice with alpha, beta, or delta variant of SARS-CoV-2, followed by treatment with the SW186 antibody. The findings revealed that mice treated with SW186 antibodies have a significantly lower viral load in the lungs compared to untreated mice. Moreover, the antibody treatment protected the mice against body weight loss, lung injury, and lung infiltration of inflammatory mediators.
To test the efficacy of the SW186 antibody in humans, a panel of humanized antibodies was generated and tested for neutralizing efficiency against alpha, beta, and delta variants. The findings revealed that most of these humanized antibodies neutralize the tested variants with similar efficacy as the murine SW186 antibody.
The study identifies a broad-spectrum monoclonal antibody (SW186) that efficiently neutralizes SARS-CoV-2 variants of concern and SARS-CoV-1. The scientists believe that the conserved RBD epitope targeted by SW186 antibody could be considered in future studies for developing novel therapeutic antibodies.